Mast cells are essential effector cells in the elicitation of the allergic responses by releasing cytoplasmic granules. Our recent studies suggest that mast cells participate in human pathobiology beyond allergic inflammation. Mast cell deficiency or pharmacological stabilization of mast cells reduces significantly the incidences of experimental atherosclerosis and abdominal aortic aneurysms in mice. As a close associated metabolic disorder of atherosclerosis and aortic aneurysms, obesity becomes not just an important scientific topic, but also a serious social problem worldwide. For the first time, we revealed accumulation of mast cells in adipose tissues from obese humans and mice. Using mast cell-deficient mouse model or anti-allergy mast cell stabilizer cromolyn, we demonstrated that mast cells are important player in obesity. Mast cell-deficient mice or those treated with cromolyn are significantly leaner than the control mice and show significant increase of glucose tolerance. Along with reduced body weight gain and increased glucose tolerance, serum levels of leptin, chemokine MCP-1, cytokine TNF-a, and obesity pertinent protease cathepsin S are also reduced in mast cell-deficient mice or those received cromolyn treatment. Although a mechanism by which mast cells contribute to obesity remains to be investigated, in vitro differentiated mast cells promote mouse pre-adipocyte differentiation. Thus, our central hypothesis is that mast cells produce pro-inflammatory cytokines and proteases to modulate the biology of adipose tissue and the extracellular matrix, thereby contributing to obesity, glucose tolerance and insulin sensitivity. Two specific aims are proposed: 1). To study the role of mast cells in body weight gain and glucose metabolism and to examine whether we can control the progression of obesity and/or reverse the phenotypes of pre-formed obesity in mice by regulating mast cell activations. 2). To identify which chemokine receptors that mast cells use for homing to the adipose tissues and to identify which of those common mast cell mediators contributes to obesity. Together, these lines of experiments should provide strong evidence of whether mast cells are required for obesity and mechanistic explanations of how mast cells might influence this common metabolic disorder. PUBLIC HEALTH RELEVANCE: Obesity is a serious public health problem that affects 30% of adults in the US. Although physical exercise and open surgery are used in the clinic to reduce the body weight, effective non-invasive therapy of obesity lacks. This proposal tests the hypothesis that pro-inflammatory mast cells are important participants of obesity, and examines thoroughly whether we can manage body weight gain by regulating mast cell activity.